- Email: [email protected]
Impact of risperidone on leptin and insulin in children and adolescents with autistic spectrum disorders
CLB-09469; No. of pages: 8; 4C: 5 Clinical Biochemistry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Clinical Biochemistry journal homepage: www.elsevier.com/locate/clinbiochem
Impact of risperidone on leptin and insulin in children and adolescents with autistic spectrum disorders Pornpen Srisawasdi a,⁎, Natchaya Vanwong b, Yaowaluck Hongkaew b, Apichaya Puangpetch b, Somlak Vanavanan a, Boontarika Intachak a, Nattawat Ngamsamut c, Penkhae Limsila c, Chonlaphat Sukasem b, Martin H. Kroll d a
Division of Clinical Chemistry, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine, Bangkok 10400, Thailand c Yuwaprasart Waithayopathum Child and Adolescent Psychiatric Hospital, Department of Mental Health Services, Ministry of Public Health, Samutprakarn 10270, Thailand d Quest Diagnostics, 3 Giralda Farms, Madison, NJ 07940, USA b
a r t i c l e
i n f o
Article history: Received 6 November 2016 Received in revised form 12 January 2017 Accepted 2 February 2017 Available online xxxx Keywords: Autistic spectrum disorders Risperidone Metabolic risk factors Diabetes Children Adolescent
a b s t r a c t Objective: To evaluate the influence of dose and duration of risperidone treatment on cardiovascular and diabetes risk biomarkers in children and adolescents with autistic spectrum disorders (ASDs). Design and methods: In this cross-sectional analysis, a total of 168 ASDs patients (89% male) treated with a risperidone-based regimen for ≥12 months were included. Blood samples were analyzed for glucose and lipid metabolic markers, adiponectin, leptin, prolactin, cortisol and high sensitive C-reactive protein. Results: The mean concentrations of glucose, insulin, prolactin and leptin and HOMA-IR significantly rose with risperidone dosage (all P b 0.025), but those of adiponectin and cortisol did not. Using regression analysis, insulin, leptin, prolactin and glucose concentrations and HOMA-IR show significant association with dosage. None of the markers except adiponectin showed dependence on duration of treatment. However, insulin and leptin concentrations and HOMA-IR clearly increased with increasing both dosage and duration. Dosage and duration of treatment had minimal effect on standard lipid profile and lipoprotein subclasses. Conclusions: Risperidone treatment disturbed glucose homeostasis and endocrine regulation (particularly leptin) in children and adolescents with ASDs, in a dose- and duration-dependent manner, being suggestive of leptin and insulin resistance mechanisms. Metabolic adverse effects, especially development of type 2 diabetes mellitus should be closely monitored, particularly in individuals receiving high doses and/or long-term risperidone treatment. © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
1. Introduction Autistic spectrum disorders (ASDs) are a complex group of neurodevelopmental disorders with onset prior to 3 years of age [1]. The worldwide prevalence of ASDs in children has increased over the past few decades, ranging from 0.07% to 1.8% [2]. Risperidone is a second-generation antipsychotic drug approved by the US Food and Drug Administration (FDA) to treat ASDs in pediatric patients. It appeared to be the most effective treatment for irritability and aggression in these patients [3–4]. In addition, there has recently been a large increase in the use of risperidone in children with a wide variety of psychiatric and non-psychiatric disorders [5–6]. Consequently, prescriptions for ⁎ Corresponding author at: Division of Clinical Chemistry, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Rama VI Road, Ratchathewi, Bangkok 10400, Thailand. E-mail address: [email protected] (P. Srisawasdi).
risperidone, in particular the off-label therapeutic use in children, have increased dramatically in many countries. Numerous studies have presented associations between antidopaminergic antipsychotic drug therapy and adverse effects, in particular rapid weight gain and metabolic and endocrine abnormalities [7–9]. Although, the specific mechanisms for the metabolic disturbances are not fully understood, children and adolescences appears to experience more adverse effects, even with shorter durations of treatment, than adults [7–8]. The presence of increased appetite during antipsychotic treatment has led investigations to consider a link between increased caloric intake, serotonin, and histamine receptors in the hypothalamus and the accumulation of adipose tissue [10]. Adipose tissue influences the regulation of several important physiological functions through adipokines, including appetite, satiety, energy expenditure, activity, insulin sensitivity and secretion, glucose and lipid metabolism, fat distribution, neuroendocrine regulation, and function of the immune system [11]. Current research proposes that
http://dx.doi.org/10.1016/j.clinbiochem.2017.02.003 0009-9120/© 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Please cite this article as: P. Srisawasdi, et al., Impact of risperidone on leptin and insulin in children and adolescents with autistic spectrum disorders, Clin Biochem (2017), http://dx.doi.org/10.1016/j.clinbiochem.2017.02.003
2
P. Srisawasdi et al. / Clinical Biochemistry xxx (2017) xxx–xxx
2. Materials and methods
using Siemens enzymatic methods (Siemens Medical Solution Diagnostics, Tarrytown, NY, USA). High-sensitivity CRP were measured on the Siemens BN Prospec using the immune nephelometric method, and adiponectin and leptin levels were quantified using a sandwich ELISA system (Mediagnost Gesellschaft für Forschung and Herstellung von Diagnostika GmbH, D-72770 Reutlingen, Germany) [18]. The insulin and prolactin levels were determined using a chemiluminescent immunoassay on the Immulite H2975 (Siemens Medical Solution Diagnostics) and the Architect ci2000 (Abbott Laboratories Abbott Park, IL, USA), respectively. Insulin resistance was estimated using the homeostasis model assessment of insulin resistance (HOMA-IR). The index of HOMA-IR was calculated according to the following formula: HOMAIR = fasting insulin (μU/mL) × fasting glucose (mmol/L) / 22.5. Patient sera were analyzed for lipoprotein subclass using polyacrylamide tube gel electrophoresis (Quantimetrix Lipoprint™, Redondo Beach, CA, USA). This method electrophoretically separates plasma lipoproteins into a maximum of 12 bands ranked by size: very low density (VLDL), midbands [primarily intermediate low density (IDL): MIDC, MIDB and MIDA], large, buoyant LDL (LDL1 and LDL2), small dense LDL (LDL3 to LDL7), and HDL. The relative area for each lipoprotein band was determined by densitometry and multiplied by the total cholesterol concentration to yield the amount of cholesterol for each band. A mean LDL-particle size was computed by integrating the relative contribution of each subfraction of LDL for a given subject.
2.1. Study subjects
2.3. Statistical analyses
A cross-sectional observational study was conducted. During May 2013 to April 2014, we enrolled 168 (149 males and 19 females) Thai children and adolescent outpatients aged between 4 and 18 years from the Yuwaprasart Waithayopathum Child and Adolescent Psychiatric Hospital, Samutprakarn, Thailand, who had been diagnosed with ASDs according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition [1]. Subjects and/or parents/legal guardians were informed of the specific risks and benefits of participation and provided their written consent. The study protocol was approved by the ethics committee of the Faculty of Medicine, Ramathibodi Hospital, Bangkok, Thailand. All participants receiving a risperidone-based regimen for one year or more were enrolled in this study. Demographics and treatment history including dosage and concomitant therapy were extracted from the medical and pharmacy records. Height, weight, and waist circumference measurements were also obtained at enrollment. Exclusion criteria for this study were a known history of pervasive developments disorders, mental retardation, schizophrenia, other psychotic disorders, or conditions associated with convulsions as well as cardiovascular disease, diabetes, cancer, end-stage chronic kidney disease or other serious physical conditions (i.e. thyroid disorders). We excluded patients receiving concomitant treatments that could potentially affect glucose and lipid metabolism. Based on FDA-approved dosing recommendations for pediatric patients [3], we categorized subjects into three groups: low-dose, recommended-dose, and high-dose groups. The recommended starting dose of risperidone is 0.25–0.5 mg/day for patients with body weight b20 kg, or 0.5–1 mg/day for those with body weight of 20 kg or greater. Patients taking less or more than these recommended amounts were classified as receiving low or high doses, respectively.
The clinical data of study subjects were expressed as the medians plus the minimum-maximum range for continuous variables. The chisquare test was used to assess the differences in patient characteristics between boys and girls. Individual group data for all biochemical markers were reported as the mean and standard error of mean (SE), and differences among groups were analyzed using one-way analysis of variance or Mann–Whitney U tests where appropriate. A multiple linear regression model was used to determine the associations between the dosage and duration of treatment and each metabolic risk biomarker. P values b 0.05 were considered statistically significant. All analyses were performed using SPSS, version 15.0 (SPSS Inc., Chicago, IL, USA).
adiponectin and leptin regulate metabolic activity, appetite, and other physiological functions, thus contributing to the development of obesity-related diseases such as type 2 diabetes mellitus (type 2 DM) and cardiovascular disease (CVD) [12]. Adiponectin is abundantly expressed in healthy individuals, has anti-thrombotic, anti-atherogenic, and anti-inflammatory properties, and is down-regulated in obese individuals [13]. Leptin plays an important role in appetite regulation by sympathetic nervous system activation impacting energy homeostasis [14]. Research suggests that antipsychotic medication may affect the common regulatory action of adipokines on appetite, contributing to the development of obesity-related diseases [10,15]. Atherosclerosis begins in childhood. As such, knowledge of the impact of treatments, such as resperidone, is essential for good longterm management of patients into adulthood [16]. Age-inappropriate weight gain and metabolic disturbance in childhood may accelerate or accentuate type 2 DM and CVD, causing premature mortality and morbidity in adults [16–17]. The aim of this cross-sectional observational study was to evaluate the influence of dosage and duration of risperidone treatment on metabolic risk markers in Thai children and adolescents with ASDs. The emphasis was on markers of energy disturbance and cardiovascular disease risk: glucose intolerance, adipokines, dyslipidemia and high-sensitivity C-reactive protein (hsCRP).
3. Results 3.1. Characteristics of the study population The demographic characteristics and biochemical test results of all participants are summarized in Table 1. The majority were male (88.7%), reflecting the more common prevalence of ASD in boys than in girls in the Thai population. More males received a high dose (1.0 mg/day) of risperidone than did females (0.5 mg/day). Median treatment duration was greater in males (62.2 months; interquartile range: 41.5–81.7 months) than females (46.7 months; interquartile range: 30.0–74.1 months). Body mass index (BMI) and waist circumferences were not significantly different between males and females. Although, the mean values of the most biomarkers did not differ significantly between genders, girls presented with greater the levels of leptin and cortisol than males. 3.2. Clinical and biochemical parameters and risperidone dosage
2.2. Biochemical measurements Blood samples were collected as serum or plasma in the fasting state, between the hours of 7 and 10 a.m. All samples were stored at 2-8 °C and analyzed within one day of collection for total cholesterol, triglycerides, low-density lipoprotein-cholesterol (LDL-C), and high-density lipoprotein-cholesterol (HDL-C), creatinine, uric acid, glucose, insulin, adiponectin, leptin, prolactin, and hsCRP. Serum total cholesterol, triglycerides, LDL-C and HDL-C and plasma glucose, were measured
Of these 168 patients, 55 (52 males and 3 females) had a daily dose above FDA recommendation (Table 2), and higher dosage correlated with longer duration. Many of the metabolic risk markers showed statistically significant differences based on the dosage. The mean concentrations of glucose intolerance (fasting glucose, insulin and HOMA-IR) as well as prolactin and leptin rose significantly with increasing daily dosage (all P ≤ 0.022), but those of adiponectin and cortisol did not. Dosage had minimal effect on lipid markers, including triglycerides, total
Please cite this article as: P. Srisawasdi, et al., Impact of risperidone on leptin and insulin in children and adolescents with autistic spectrum disorders, Clin Biochem (2017), http://dx.doi.org/10.1016/j.clinbiochem.2017.02.003
P. Srisawasdi et al. / Clinical Biochemistry xxx (2017) xxx–xxx Table 1 Clinical parameters and biomarker levels.a
Clinical parameter, mean (range) Age, years
Table 2 Clinical and biochemical parameters and risperidone dosage.a
All (n = 168)
Male (n = 149)
Female (n = 19)
10.0 (4.7–17.9) 5.1 (1.8–16.5) 1.0 (0.1–4.0)
10.0 (4.7–17.9) 5.0 (1.8–16.5) 1.0 (0.1–4.0)
10.8 (5.0–16.3) 5.6 (3.0–15.0) 0.5 (0.1–2.0)
0.905
62.2 (17.5–153.6) 19.7 (10.6–38.7) 70.0 (47.0–112.0)
46.7 (14.6–121.3) 16.8 (12.4–35.6) 75.0 (48.5–114.0)
0.146
5.23 (0.04) 8.15 (0.67) 1.911 (0.162) 19.41 (1.24) 8.58 (0.86) 35.7 (2.2) 1.04 (0.04) 4.52 (0.07)
5.12 (0.09) 7.80 (1.79) 1.858 (0.429) 27.23 (7.74) 10.70 (2.87) 35.8 (4.4) 1.01 (0.08) 4.55 (0.20)
0.354 0.971 0.912
1.41 (0.03) 2.81 (0.06)
1.46 (0.10) 2.78 (0.17)
0.641 0.874
0.72 (0.02) 0.45 (0.02) 0.26 (0.01) 0.37 (0.01) 0.91 (0.02) 0.49 (0.02) 0.12 (0.02) 26.93 (0.03) 8.93 (0.46) 2.288 (0.303)
0.63 (0.02) 0.45 (0.03) 0.28 (0.02) 0.39 (0.04) 1.02 (0.07) 0.50 (0.04) 0.09 (0.02) 26.94 (0.09) 12.69 (0.96) 2.292 (1.271)
0.043 0.910 0.551 0.586 0.098 0.889 0.588 0.892 0.005 0.996
Age at starting risperidone, years Risperidone dose, mg/day Duration of treatment, 60.7 months (14.6–153.6) 2 Body mass index, kg/m 19.6 (10.6–38.7) Waist circumference, 70.0 cm (47.0–114.0) Biomarker Fasting glucose, mmol/L 5.22 (0.04) Insulin, μIU/mL 8.14 (0.63) HOMAIR 1.905 (0.151) Prolactin, ng/mL 20.25 (1.38) Leptin, ng/mL 8.85 (0.83) Adiponectin, μg/mL 35.7 (2.0) Triglycerides, mmol/L 1.04 (0.04) Total cholesterol, 4.52 (0.06) mmol/L HDL-C, mmol/L 1.42 (0.03) LDL-C, mmol/L 2.80 (0.06) Lipoprotein subclass (mmol/L) VLDL 0.71 (0.02) MIDC 0.45 (0.01) MIDB 0.26 (0.01) MIDA 0.37 (0.01) LDL1 0.92 (0.02) LDL2 0.50 (0.02) LDL3 to LDL7 0.11 (0.01) LDL-particle size (nm) 26.93 (0.03) Cortisol, μg/dL 9.39 (0.44) hsCRP, mg/L 2.288 (0.303)
3
Risperidone dosage P-value
0.169 0.027
0.275 0.496
0.079 0.402 0.989 0.805 0.880
All biochemical measures are given in Système International units; conversions to conventional units are as follows: fasting glucose (mg/dL), multiply by 18.02, cholesterol (mg/dL), multiply by 38.6, triglycerides (mg/dL), multiply by 88.5. HOMAIR, homeostasis model assessment of insulin resistance; HDL-C, high density lipoprotein-cholesterol; LDL-C, low density lipoprotein–cholesterol; VLDL, very low density lipoprotein; MID, intermediate density lipoprotein midband; hsCRP, high sensitivity Creactive protein. a Data are given as median (minimum-maximum) for clinical parameters and mean (SE) for biomarkers.
cholesterol, HDL-C, LDL-C, and lipoprotein subclasses (all P N 0.10). Although BMI did not vary significantly with risperidone dosage overall, patients treated with a high risperidone dose had a greater mean BMI (22.14 kg/m2) than those treated with a low dose (18.52 kg/m2). Based on comparison between low-dose with high-dose group, leptin shows the highest response, a 270% increase followed by prolactin, a 161% increase, HOMA-IR, a 136% increase, insulin, a 129% increase, adiponectin, a 35% decrease, triglycerides, a 25% increase, HDL-C, a 14% decrease, and glucose, a 5% increase. 3.3. Clinical and biochemical parameters and duration of risperidone therapy We stratified patients into four groups based on the duration of risperidone therapy. The mean dose and BMI markedly increased with long-term risperidone treatment (Table 3). The mean of insulin concentration and HOMA-IR significantly differed among the four groups (all P b 0.025), increasing with longer duration, but fasting glucose did not. Levels of all lipid markers including triglycerides, total cholesterol, HDL-C, LDL-C as well as lipoprotein subclasses did not change
Low dose (n = 18) Clinical parameter Age, years Risperidone dose, mg/day Duration of treatment, months Body mass index, kg/m2 Biomarker Fasting glucose, mmol/L Insulin, μIU/mL HOMAIR Prolactin, ng/mL Leptin, ng/mL Adiponectin, μg/mL Triglycerides, mmol/L Total cholesterol, mmol/L HDL-C, mmol/L LDL-C, mmol/L Lipoprotein subclass (mmol/L) VLDL MIDC MIDB MIDA LDL1 LDL2 LDL3 to LDL7 LDL-particle size (nm) Cortisol, μg/dL hsCRP, mg/L
Recommended dose (n = 95)
9.20 (0.76) 10.86 (0.35)
P-value High dose (n = 55)
11.61 (0.49) 2.066 (0.109) 74.07 (4.11) 22.14 (0.81)
0.056
0.017 0.017
49.3 (7.5) 34.9 (2.5) 0.85 (0.07) 1.06 (0.05) 4.49 (0.20) 4.58 (0.09)
5.29 (0.07) 10.24 (1.31) 2.369 (0.302) 25.06 (2.65) 12.40 (1.85) 32.1 (3.1) 1.06 (0.07) 4.43 (0.10)
1.57 (0.11) 1.43 (0.04) 2.68 (0.17) 2.82 (0.08)
1.35 (0.05) 0.102 2.82 (0.10) 0.777
0.65 (0.02) 0.41 (0.05) 0.25 (0.02) 0.38 (0.03) 0.92 (0.07) 0.48 (0.05) 0.11 (0.02) 26.93 (0.06) 8.52 (0.97) 4.913 (1.910)
0.69 (0.03) 0.45 (0.02) 0.25 (0.01) 0.34 (0.02) 0.90 (0.03) 0.52 (0.03) 0.12 (0.02) 26.91 (0.04) 9.96 (0.81) 2.781 (0.482)
0.253 (0.020) 54.50 (6.59) 18.52 (1.29)
0.751 (0.026) 59.74 (3.11) 20.38 (0.62)
4.92 (0.12) 5.24 (0.04) 4.46 (0.92) 7.71 (0.78) 1.002 1.832 (0.195) (0.217) 11.53 19.11 (1.79) (2.21) 3.35 (1.01) 8.06 (0.94)
0.73 (0.02) 0.46 (0.02) 0.27 (0.01) 0.38 (0.02) 0.93 (0.03) 0.48 (0.02) 0.11 (0.02) 26.94 (0.04) 9.23 (0.60) 1.502 (0.249)
b0.001 0.009 0.058
0.022 0.012 0.003 0.035 0.181 0.589
0.146 0.615 0.418 0.240 0.809 0.558 0.969 0.912 0.597 0.001
Abbreviations as in Table 1. a Data are given as mean (SE).
significantly with duration of therapy. Leptin and hsCRP concentrations increased with duration, although the variation in hsCRP was not statistically significant. Prolactin and cortisol concentrations were not significantly different among treatment duration groups. Based on comparison between duration treatment of less than or = to 24 months with over 96 months, leptin shows the highest response, a 118% increase followed by prolactin, a 113% increase, insulin, a 109% increase, HOMA-IR, a 109% increase, adiponectin, a 57% decrease, triglycerides, a 57% increase, HDL-C, a 20% decrease, and glucose, a 2% decrease. 3.4. Association of dosage and duration of risperidone treatment with metabolic risk markers Table 4 shows the regression coefficients and 95% confidence intervals of dosage and duration of risperidone treatment for biomarkers after adjusting for gender, age and BMI. Insulin, leptin, prolactin, fasting glucose concentrations and HOMA-IR show the significant association with the amount of risperidone dose, while adiponectin, triglycerides, HDL-C and hsCRP did not. None of the markers except adiponectin showed dependence on duration of risperidone treatment in pediatric patients. In addition, we found BMI exerted the strong association
Please cite this article as: P. Srisawasdi, et al., Impact of risperidone on leptin and insulin in children and adolescents with autistic spectrum disorders, Clin Biochem (2017), http://dx.doi.org/10.1016/j.clinbiochem.2017.02.003
4
P. Srisawasdi et al. / Clinical Biochemistry xxx (2017) xxx–xxx
Table 3 Clinical and biochemical parameters and duration of risperidone therapy.a Duration period of risperidone (months)
Clinical parameter Age, years Duration of treatment, months Risperidone dose, mg/day Body mass index, kg/m2 Biomarker Fasting glucose, mmol/L Insulin, μIU/mL HOMAIR Prolactin, ng/mL Leptin, ng/mL Adiponectin, μg/mL Triglycerides, mmol/L Total cholesterol, mmol/L HDL-C, mmol/L LDL-C, mmol/L Lipoprotein subclass (mmol/L) VLDL MIDC MIDB MIDA LDL1 LDL2 LDL3 to LDL7 LDL-particle size (nm) Cortisol, μg/dL hsCRP, mg/L
P-value
0–24 (n = 11)
N24–48 (n = 46)
N48–96 (n = 83)
N96 (n = 28)
7.40 (1.00) 19.72 (0.88) 0.735 (0.158) 17.33 (1.37)
8.95 (0.44) 34.85 (1.04) 0.829 (0.074) 17.26 (0.50)
11.10 (0.30) 68.66 (1.34) 1.297 (0.108) 21.80 (0.70)
14.84 (0.45) 114.70 (3.64) 1.352 (0.169) 24.75 (1.10)
b0.001 b0.001 0.004 b0.001
5.26 (0.12) 5.221 (1.149) 1.216 (0.282) 16.26 (3.94) 6.43 (2.25) 40.1 (7.7) 0.78 (0.08) 4.72 (0.17) 1.57 (0.11) 2.83 (0.19)
5.21 (0.08) 5.555 (0.763) 1.266 (0.166) 22.73 (3.26) 5.98 (1.12) 42.6 (3.6) 1.00 (0.05) 4.75 (0.14) 1.49 (0.06) 2.90 (0.11)
5.27 (0.06) 9.040 (0.876) 2.144 (0.219) 19.64 (1.96) 9.40 (1.27) 36.4 (2.9) 1.05 (0.05) 4.42 (0.09) 1.40 (0.04) 2.71 (0.08)
5.09 (0.09) 10.584 (2.145) 2.453 (0.503) 19.57 (2.09) 13.99 (2.41) 18.1 (2.0) 1.19 (0.11) 4.37 (0.15) 1.27 (0.06) 2.91 (0.16)
0.437 0.021 0.021 0.670 0.019 0.001 0.062 0.107 0.064 0.491
0.68 (0.07) 0.40 (0.03) 0.28 (0.03) 0.45 (0.05) 1.00 (0.05) 0.49 (0.07) 0.07 (0.02) 27.06 (0.06) 10.12 (0.76) 0.862 (0.268)
0.74 (0.03) 0.50 (0.03) 0.29 (0.02) 0.39 (0.02) 0.95 (0.04) 0.50 (0.03) 0.12 (0.04) 26.93 (0.06) 9.20 (0.79) 1.506 (0.554)
0.69 (0.02) 0.44 (0.02) 0.25 (0.01) 0.35 (0.02) 0.89 (0.03) 0.49 (0.02) 0.12 (0.02) 26.89 (0.04) 8.84 (0.63) 2.677 (0.442)
0.72 (0.04) 0.41 (0.02) 0.26 (0.01) 0.36 (0.02) 0.94 (0.05) 0.51 (0.05) 0.11 (0.02) 26.98 (0.04) 11.54 (1.34) 3.007 (0.841)
0.620 0.070 0.077 0.087 0.495 0.986 0.791 0.350 0.243 0.167
Abbreviations as in Table 1. a Data are given as mean (SE).
Table 4 Association of BMI, dose and duration period of risperidone with metabolic risk factors. Dependent variable Insulin BMI Risperidone dose, mg/day Duration of treatment, months HOMAIR BMI Risperidone dose, mg/day Duration of treatment, months Leptin BMI Risperidone dose, mg/day Duration of treatment, months Adiponectin BMI Risperidone dose, mg/day Duration of treatment, months Prolactin BMI Risperidone dose, mg/day Duration of treatment, months Glucose BMI Risperidone dose, mg/day Duration of treatment, months hsCRP BMI Risperidone dose, mg/day Duration of treatment, months a
Regression coefficienta
95% confidence interval
P-value
0.602 1.597 0.034
0.391 to 0.813 0.081 to 3.113 −0.018 to 0.087
b0.001 0.039 0.195
0.143 0.402 0.009
0.091 to 0.194 0.031 to 0.773 −0.003 to 0.022
b0.001 0.034 0.149
1.256 1.958 0.000
1.072 to 1.439 0.584 to 3.332 −0.046 to 0.046
b0.001 0.006 0.995
−1.702 2.047 −0.206
−2.326 to −1.078 −2.662 to 6.756 −0.363 to −0.050
b0.001 0.391 0.010
0.025 5.372 −0.055
−0.496 to 0.547 1.817 to 8.926 −0.189 to 0.079
0.923 0.003 0.420
0.124 2.496 0.012
−0.133 to 0.381 0.743 to 4.250 −0.054 to 0.078
0.369 0.005 0.800
0.280 0.134 0.009
0.169 to 0.391 −0.651 to 0.919 −0.020 to 0.037
b0.001 0.736 0.535
Data are from multivariable linear regression analyses, adjusted for gender and age.
with the concentrations of insulin, leptin, adiponectin, triglycerides, HDL-C and hsCRP but not with prolactin and fasting glucose concentrations. 3.5. Effect of dosage and duration of risperidone treatment on metabolic risk markers To assess the effect of both dosage and duration of treatment on metabolic risk factors, the geometric means of each marker concentration based on the administration of low-dose, recommended-dose and high-dose in four duration groups were calculated (Fig. 1). No subject in the high-dose group had been treated for less than or = to 24 months. A similar pattern occurred with insulin (Fig. 1A) and leptin (Fig. 1C) concentration and HOMA-IR (Fig. 1B), all clearly increased with dosage and duration. The geometric mean of prolactin level (Fig. 1E) was higher in the high-dose than in the low-dose, especially in the group treated for 48 to 96 months (P-value = 0.004) and was not associated with duration. Similar findings were seen with fasting glucose concentration (Fig. 1F). The geometric means of adiponectin (Fig. 1D) appeared decreasing with duration. Risperidone dosage increases the percentage of subjects who exceed age-specific reference intervals for glucose, insulin resistance, leptin, triglycerides and HDL-C (Table 5). Also, risperidone duration causes the same effects for leptin (Table 5). For both dosage and duration, the increases are significant. 4. Discussion Risperidone is a drug widely prescribed for children and adolescents with ASDs. Discontinuation is associated with resurgence of aggression, so long-life medication is recommended [22]. Because of differences in absorption, distribution, and metabolism, children require a higher dose per kilogram weight to achieve efficacy similar to that in adults [8]. Little is known about potential dose and duration-related effects of
Please cite this article as: P. Srisawasdi, et al., Impact of risperidone on leptin and insulin in children and adolescents with autistic spectrum disorders, Clin Biochem (2017), http://dx.doi.org/10.1016/j.clinbiochem.2017.02.003
P. Srisawasdi et al. / Clinical Biochemistry xxx (2017) xxx–xxx
5
Fig. 1. Effect of dosage and duration of risperidone treatment on metabolic risk markers.
risperidone medication on metabolic, diabetes, and endocrine disturbances in these vulnerable populations. With regards to risperidone-induced endocrine disturbances, increased prolactin has been the most common observation [23]. As expected, in our subjects, we observed prolactin elevations associated with dose. Besides prolactin, the dose significantly and clinically affected glucose, insulin, HOMA-IR, and leptin, independent of BMI (Table 4). Although, long-term therapy increased leptin, insulin, and HOMA-IR, the results were not statistically significant with the duration after adjusting for age, gender and BMI. Adiponectin showed a decrease,
dependent on duration, but not dose, suggesting that the mechanism for action works indirectly by decreasing satiety and ultimately increasing food intake, thus resulting in increased body adiposity. Studies suggest increase in appetite results in increased adipose tissue followed by metabolic impairments [7–8]. According to Teff KL et al., short-term administration of olanzapine and aripiprazole directly affects tissue function, enhancing peripheral insulin resistance, independent of weight gain in healthy subjects [24]. In a study on eating behavior, they found antipsychotic-induced metabolic changes preceded decreasing satiety, which they thought was caused by central insulin
Table 5 Percentage of patients exceeded age-specific reference intervals of metabolic risk biomarkers.
Hyperglycemiaa, % Increased insulin resistanceb, % Hyperleptinemiac, % TG ≥1.70 mmol/Ld, % HDL-C b 1.03 mmol/Le, % a b c d e
All (n = 168)
Risperidone dosage
Duration period of risperidone (months)
Low dose (n = 18)
Recommended dose (n = 95)
High dose (n = 55)
0–24 (n = 11)
N24–48 (n = 46)
N48–96 (n = 83)
N96 (n = 28)
22.6 22.7 45.8 9.5 16.1
11.1 11.1 28.6 0 11.1
19.0 20.5 44.9 9.4 16.8
32.7 30.6 54.1 12.73 16.4
18.2 22.2 28.6 0 18.2
21.7 17.5 44.4 2.2 10.9
24.1 25.7 45.0 12.0 18.1
21.4 22.2 58.8 17.9 17.9
Defined using the International Diabetes Federation (IDF) [19] as glucose ≥5.6 mmol/L. Defined as HOMA-IR ≥95th percentile age-specific reference intervals [20]. Defined as leptin ≥95th percentile age, sex and BMI-specific reference intervals [18,21]. Defined using the International Diabetes Federation (IDF) [19] as triglycerides ≥1.7 mmol/L. Defined using the International Diabetes Federation (IDF) [19] as HDL-C b 1.03 mmol/L.
Please cite this article as: P. Srisawasdi, et al., Impact of risperidone on leptin and insulin in children and adolescents with autistic spectrum disorders, Clin Biochem (2017), http://dx.doi.org/10.1016/j.clinbiochem.2017.02.003
6
P. Srisawasdi et al. / Clinical Biochemistry xxx (2017) xxx–xxx
and leptin resistance [25]. Here, based on our study in children and adolescents ASDs with long-term risperidone treatment, the data indicate that risperidone dosage is strongly associated with increased leptin and insulin, but not with adiponectin and BMI. Moreover, in response to risperidone treatment, based on comparison between low-dose and highdose, leptin markedly increased (270%) while adiponectin decreased (35%). Based on the comparison between duration treatment of less than or = to 24 months with over 96 months, leptin also markedly increased (118%) and adiponectin decreased (57%). It is well known that circulating leptin as well as adiponectin levels are considered to be proportional to adipose tissue mass. Consequently, we suggest that risperidone acts through leptin and insulin pathways independent of body adiposity. Risperidone appears to interfere with the leptin regulatory system, because the leptin is increased but the actions of leptin, appetite decrease and increased adipose tissue utilization, are hampered. Even though risperidone may cause increased fat deposition, as indicated by the increase in BMI, the marked increase in leptin along with weight-gain suggests that a potential mechanism may work through the development of leptin resistance. Risperidone may act directly or indirectly on the leptin receptor. Cheng et al. have demonstrated that palmitic acid in mice can inhibit leptin signaling in the paraventricular nucleus of the hypothalamus, induces an inflammatory response in the hypothalamus, and attenuate the central leptin regulation on hepatic glucose and lipid metabolism [26]. In a similar fashion, arachidonic acid reduces central leptin sensitivity, inhibits leptin signaling in the paraventricular nucleus of the hypothalamus, stimulates pro-inflammatory responses in the same area, and attenuates the central leptin action on hepatic glucose and lipid metabolism [27]. Risperidone may share some structural similarities to palmitic or arachidonic acid and thus mimic these two molecules ability to cause leptin resistance. In patients treated with second generation antipsychotics, numerous studies demonstrated that the link of increased appetite to weight gain may be explained by interaction with dopamine receptors [28]. A homeostatic mechanism for coordinating the status of energy stores is relayed by neurohormones, which are modulated by leptin and insulin. Neurohormones coordinate energy stores acting through insulin and leptin, which share receptors; consequently, risperidone may impair both hormonal actions [29–30]. The mechanism of risperidone-induced insulin and leptin resistance may act through the inhibition of dopamine D2 receptors regulating intercellular cyclic adenosine 3monophosphate accumulation, inhibiting insulin-induced protein kinase B phosphorylation and activation of transcription 3-phosphorylation [31]. The concept of leptin resistance is analogous to the syndrome of insulin resistance, in which elevated levels of leptin could result in the false perception that fat stores are inadequate, leading to increased food consumption. Additional adipose tissue by exceeding the level of energy intake over the level of energy expenditure will provide a worsening of the leptin and insulin resistance. Furthermore, leptin has several effects on the glucose-insulin homeostasis, such as directly regulating pancreatic β-cells and insulin-sensitive tissues, independently of its effects on adiposity [32]. Consequently, the failure of elevated leptin levels to suppress food intake and energy expenditure may promote insulin resistance in risperidone-treated patients. An alteration of adipokines and increased insulin and leptin resistances resulted in a vicious cycle of increased adipose tissue and leptin and insulin resistance. In our study, we found the mean concentration of leptin in boys was lower than in girls which is consistent with other studies [33–34]. Garcia-Mayor et al. reported the age-related changes of leptin in healthy boys after the age of 10 years declines as testosterone increases [33]. In the present work, the levels of leptin rose progressively in chronically treated patients (the mean age of 15.04 years) with high risperidone dose (Fig. 1). Interestingly, a similar pattern occurred with insulin levels. It appears treatment disturbs the leptin and insulin regulatory systems, in a dose- and duration-dependent manner, suggesting that both
hormones are the key agents of interest. Because strong associations link leptin, insulin, HOMA-IR and adiponectin with BMI (Table 4), a complex network exists, supporting the concept that risperidone plays a role in appetite regulation and the communication of energy needs between the central nervous system and adipose tissue resulting in individual weight gain [35]. Despite the evidence of insulin resistance among Thai children and adolescent ASDs treated with risperidone, evidence of type 2 DM as defined by fasting plasma glucose ≥7.0 mmol/L (to convert to mg/dL, multiply by 18.02) was not observed with therapy up to 153.6 months. Glucose showed a slight response to risperidone treatment, changing only 2–8%. The failure of glucose to change in value, while insulin increases strongly, suggests insulin resistance, which may represent a pre-diabetec state. This is not surprising given that the development of type 2 DM is a progressive process that manifests over many years and perhaps decades [36]. Nevertheless, we found a clear association between dose and plasma glucose, consistent with global studies in pediatric populations [17,37]. The alteration of glucose homeostasis in childhood causes a rapid onset of type 2 DM later in adulthood. Interestingly, our results indicated that the concentration of fasting plasma glucose was not significantly related with BMI. It is, thus, tempting to assume that treated-risperidone among children and adolescents with the particular high-doses and long-term medication may induce a high rate in development of type 2 DM that might potentially occur without change in body weight. Risperidone dosage showed a limited effect while duration a mild effect on BMI (Tables 2 and 3). Such a response could be aligned with the lower prevalence of metabolic syndrome in the adult Asian population [38]. Patients with low dose or duration risperidone did not exceed age-specific interval for triglycerides (Table 5). In contrast, even at low dose or duration, the percentage of subjects with hyperglycemia and increased insulin resistance (markers of prediabetes) was increased (Table 5). The most alarming finding was that at high-dose or long-duration risperidone treatment, the percentage of subjects exceeding the age-specific reference intervals was N50% (Table 5). Both insulin and leptin resistance contribute to cardio-metabolic risk by disturbing of carbohydrate and lipid metabolism [39]. Besides diabetes, dyslipidemia is of concern upon the administration of antipsychotic drugs in children and adolescents. Triglycerides and HDL-C are the main lipid biomarkers for cardiometabolic risk during antipsychotics treatment [7]. Interestingly, our results did not show significant changes for triglycerides, HDL-C, and small dense LDL in association with dosage and duration treatment of risperidone in youths with ASDs. Moreover, most patients had plasma lipid and lipoprotein concentrations similar to that of general healthy population. We observed an increase triglycerides and decrease in HDL with longer duration of treatment (Table 3). Thus, it is possible that resperidone-induced insulin and leptin resistances may influence cardiometabolic pathways. In addition, significant weight gain appeared to be more prevalence in these patients, perhaps based on obesity playing a central role among metabolic disturbances including insulin resistance, hypertension and inflammation. Consequently, drug-induced metabolic abnormality in childhood may enhance a development of cardiometabolic disorders later in adulthood. Limitations of this study include that it was cross-sectional in design and based on an Asian population. Longitudinal observations in drugnaïve patients that will be adequately powered for demonstrating an association of risperidone therapy and metabolic side effects is warranted. The study did not include other ethnicities. It is possible that ethnicity and individual-specific thresholds might be haven different genetic variant for metabolize of risperidone in pediatric patients. A major metabolizing enzyme of risperidone is cytochrome P 2D6 [40], thus, presence of its various phenotypes can lead to decrease or elevate metabolism and elimination of risperidone which may contribute to drug-increased metabolic adverse effects. Future studies including other ethnicities and individual-pharmacogenomic of risperidone may provide additional information.
Please cite this article as: P. Srisawasdi, et al., Impact of risperidone on leptin and insulin in children and adolescents with autistic spectrum disorders, Clin Biochem (2017), http://dx.doi.org/10.1016/j.clinbiochem.2017.02.003
P. Srisawasdi et al. / Clinical Biochemistry xxx (2017) xxx–xxx
In conclusion, risperidone dose in the treatment for autistic spectrum disorders in children and adolescents affect leptin and insulin. Our findings highlight that risperidone therapy directly and adversely impacts glucose homeostasis by inhibiting the actions of leptin and insulin. Risperidone-induced abnormalities in leptin and insulin resistance result in adipose tissue accumulation, which in turn can lead to complications of lipid metabolism and cardiovascular disease. These effects are related to treatment dose. The adverse metabolic changes associated with risperidone treatment suggest that risk for metabolic adverse effects, especially development of type 2 diabetes mellitus and adipose regulation should be closely monitored, particularly in patients receiving high doses and long-term treatment. Because of interindividual variability in risperidone metabolism, the resulting plasma concentration at a given dose cannot be predicted by the dose. Thus, the monitoring its level would affords the opportunity to limit long term impact of these side effects. In addition, pursuit of therapeutic interventions that specifically enhance the actions of leptin and insulin could improve patient management and reduce the risk of cardiovascular complications.
[8]
[9]
[10]
[11] [12] [13]
[14]
[15]
[16]
Funding [17]
This study was supported by research grants of 1) the Faculty of Medicine, Ramathibodi Hospital, Mahidol University (56076), Thailand, 2) Khun Poom Foundation, a project under Her Royal Highness Princess Ubonratana Rajakanya Siriwatana Bhanawadee and 3) the National Research Council of Thailand (92/2558).
[18] [19] [20]
Conflicts of interest [21]
The authors declare no conflicts of interest related to this article. [22]
Author contributions All authors confirm they have contributed to the intellectual content of this paper and have met the following requirements: (a) providing a significant contribution to the conception, design and conduct of the study and the data collection, analysis and interpretation; (b) participating in the drafting or revision of the article for intellectual content; and (c) granting final approval of the article.
[23]
[24]
[25]
[26]
Acknowledgments The authors gratefully acknowledge the staff of Yuwaprasart Waithayopathum Child and Adolescent Psychiatric Hospital and Jirapa Kerdmongkol at the Department of Pathology, Ramathibodi Hospital, Mahidol University for their assistance. We wish to thank all the children and adolescents with ASDs who took part in this study. References [1] American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders (4th ed., text revision), American Psychiatric Association, Washington, DC, 2000 70–75. [2] Centers for Disease Control and Prevention, Prevalence of autism spectrum disorders—Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008, MMWR Surveill. Summ. 61 (3) (Mar 30, 2012) 1–19. [3] FDA Approves the First Drug to Treat Irritability Associated With Autism, Risperdal, US Food and Drug Administration, April 5, 2013 Web site. http://www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/2006/ucm108759.htm. Updated. (Accessed June 24, 2016). [4] A. Gagliano, E. Germanò, G. Pustorino, et al., Risperidone treatment of children with autistic disorder: effectiveness, tolerability, and pharmacokinetic implications, J Child Adolesc Psychopharmacol 14 (1) (2004) 39–47. [5] R.B. Penfold, C. Stewart, E.M. Hunkeler, et al., Use of antipsychotic medications in pediatric populations: what do the data say? Curr. Psychiatry Rep. 15 (12) (2013) 426. [6] L. Carton, O. Cottencin, M. Lapeyre-Mestre, et al., Off-label prescribing of antipsychotics in adults, children and elderly individuals: a systematic review of recent prescription trends, Curr. Pharm. Des. 21 (23) (2015) 3280–3297. [7] M. De Hert, M. Dobbelaere, E.M. Sheridan, et al., Metabolic and endocrine effects of second-generation antipsychotic in children and adolescents: a systematic review of
[27] [28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
7
randomized, placebo controlled trials and guidelines for clinical practice, Eur. Psychiatry 26 (3) (2011) 144–158. R. Ronsley, D. Nguyen, J. Davidson, et al., Increased risk of obesity and metabolic dysregulation following 12 months of second-generation antipsychotic treatment in children: a prospective cohort study, Can. J. Psychiatr. 60 (10) (2015) 441–450. D.M. Rubin, A.R. Kreider, M. Matone, et al., Risk for incident diabetes mellitus following initiation of second-generation antipsychotics among Medicaid-enrolled youths, JAMA Pediatr. 169 (4) (2015), e150285. L.A. Maayan, J. Vakhrusheva, Risperidone associated weight, leptin, and anthropometric changes in children and adolescents with psychotic disorders in early treatment, Hum. Psychopharmacol. 25 (2) (2010) 133–138. H.K. Park, R.S. Ahima, Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism, Metabolism 64 (1) (2015) 24–34. Y. Matsuzawa, Establishment of a concept of visceral fat syndrome and discovery of adiponectin, Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 86 (2) (2010) 131–141. A. Alikaşifoğlu, N. Gönç, Z.A. Özön, et al., The relationship between serum adiponectin, tumor necrosis factor-alpha, leptin levels and insulin sensitivity in childhood and adolescent obesity: adiponectin is a marker of metabolic syndrome, J. Clin. Res. Pediatr. Endocrinol. 1 (5) (2009) 233–239. H.S. Moon, M. Dalamaga, S.Y. Kim, et al., Leptin's role in lipodystrophic and nonlipodystrophic insulin-resistant and diabetic individuals, Endocr. Rev. 34 (3) (2013) 377–412. Z.J. Zhang, Z.J. Yao, W. Liu, et al., Effects of antipsychotics on fat deposition and changes in leptin and insulin levels. Magnetic resonance imaging study of previously untreated people with schizophrenia, Br. J. Psychiatry 184 (2004) 58–62. M. De Hert, J. Detraux, R. van Winkel, et al., Metabolic and cardiovascular adverse effects associated with antipsychotic drugs, Nat. Rev. Endocrinol. 8 (2) (2011) 114–126. W.V. Bobo, W.O. Cooper, C.M. Stein, et al., Antipsychotics and the risk of type 2 diabetes mellitus in children and youth, JAMA Psychiat. 70 (10) (2013) 1067–1075. Leptin, Mediagnost Gesellschaft für Forschung and Herstellung von Diagnostika, Leptin Sensitive ELISA Assay Kit product No. E077. GmbH, D-72770 Reutlingen, Germany. P. Zimmet, K.G. Alberti, F. Kaufman, et al., The metabolic syndrome in children and adolescents – an IDF consensus report, Pediatr. Diabetes 8 (2007) 299–306. P. Allard, E.E. Delvin, G. Paradis, et al., Distribution of fasting plasma insulin, free fatty acids, and glucose concentrations and of homeostasis model assessment of insulin resistance in a representative sample of Quebec children and adolescents, Clin. Chem. 49 (4) (2003) 644–649. N. Kiatsopit, O. Panamonta, C. Suesirisawat, et al., The age of onset of pubertal development in healthy Thai boys in Khon Kaen, Thailand, Asian Biomed. 9 (2) (2015) 225–229. Research Units on Pediatric Psychopharmacology Autism Network, Risperidone treatment of autistic disorder: longer-term benefits and blinded discontinuation after 6 months, Am. J. Psychiatry 162 (7) (2005) 1361–1369. Y. Roke, P.N. van Harten, A.M. Boot, J.K. Buitelaar, Antipsychotic medication in children and adolescents: a descriptive review of the effects on prolactin level and associated side effects, J. Child Adolesc. Psychopharmacol. 19 (4) (2009) 403–414. K.L. Teff, M.R. Rickels, J. Grudziak, et al., Antipsychotic-induced insulin resistance and postprandial hormonal dysregulation independent of weight gain or psychiatric disease, Diabetes 62 (9) (2013) 3232–3240. K.L. Teff, K. Rickels, E. Alshehabi, et al., Metabolic impairments precede changes in hunger and food intake following short-term administration of second-generation antipsychotics, J. Clin. Psychopharmacol. 35 (5) (2015) 579–582. L. Cheng, Y. Yu, A. Szabo, et al., Palmitic acid induces central leptin resistance and impairs hepatic glucose and lipid metabolism in male mice, J. Nutr. Biochem. 26 (5) (2015) 541–548. L. Cheng, Y. Yu, H. Wang, et al., Arachidonic acid impairs hypothalamic leptin signaling and hepatic energy homeostasis in mice, Mol. Cell. Endocrinol. 412 (2015) 12–18. A. Esen-Danaci, A. Sarandol, F. Taneli, et al., Effects of second generation antipsychotics on leptin and ghrelin, Prog. Neuro-Psychopharmacol. Biol. Psychiatry 32 (6) (2008) 1434–1438. K.D. Niswender, D.G. Baskin, M.W. Schwartz, Insulin and its evolving partnership with leptin in the hypothalamic control of energy homeostasis, Trends Endocrinol. Metab. 15 (8) (2004) 362–369. C. Kursungoz, M. Ak, T. Yanik, Effects of risperidone treatment on the expression of hypothalamic neuropeptide in appetite regulation in Wistar rats, Brain Res. 1596 (2015) 146–155. L. Piao, J. Park, Y. Li, et al., SOCS3 and SOCS6 are required for the risperidone-mediated inhibition of insulin and leptin signaling in neuroblastoma cells, Int. J. Mol. Med. 33 (5) (2014) 1364–1370. S.D. Covey, R.D. Wideman, C. McDonald, et al., The pancreatic beta cell is a key site for mediating the effects of leptin on glucose homeostasis, Cell Metab. 4 (4) (2006) 291–302. R.V. Garcia-Mayor, M.A. Andrade, M. Rios, et al., Serum leptin levels in normal children: relationship to age, gender, body mass index, pituitary-gonadal hormones, and pubertal stage, J. Clin. Endocrinol. Metab. 82 (9) (1997) 2849–2855. C.S. Mantzoros, J.S. Flier, A.D. Rogol, A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. V. Rising leptin levels may signal the onset of puberty, J. Clin. Endocrinol. Metab. 82 (4) (1997) 1066–1070. M. Cnop, M.J. Landchild, J. Vidal, et al., The concurrent accumulation of intra-abdominal and subcutaneous fat explains the association between insulin resistance and plasma leptin concentrations: distinct metabolic effects of two fat compartments, Diabetes 51 (4) (2002) 1005–1015. J.B. Meigs, D.C. Muller, D.M. Nathan, et al., Baltimore longitudinal study of aging the natural history of progression from normal glucose tolerance to type 2 diabetes in the Baltimore longitudinal study of aging, Diabetes 52 (5) (2003) 1475–1484.
Please cite this article as: P. Srisawasdi, et al., Impact of risperidone on leptin and insulin in children and adolescents with autistic spectrum disorders, Clin Biochem (2017), http://dx.doi.org/10.1016/j.clinbiochem.2017.02.003
8
P. Srisawasdi et al. / Clinical Biochemistry xxx (2017) xxx–xxx
[37] C. Panagiotopoulos, R. Ronsley, J. Davidson, Increased prevalence of obesity and glucose intolerance in youth treated with second-generation antipsychotic medications, Can. J. Psychiatr. 54 (11) (2009) 743–749. [38] R.B. Khalil, Atypical antipsychotic drugs, schizophrenia, and metabolic syndrome in non-Euro-American societies, Clin. Neuropharmacol. 35 (2012) 141–147.
[39] H. Zuo, Z. Shi, B. Yuan, et al., Association between serum leptin concentrations and insulin resistance: a population-based study from China, PLoS One 8 (1) (2013), e54615. [40] J. van der Weide, J. van Baalen-Benedek, E.H. Kootstra-Ros, et al., Metabolic ratios of psychotropics as indication of cytochrome P450 2D6/2C19 genotype, Ther. Drug Monit. 27 (4) (2005) 478–483.
Please cite this article as: P. Srisawasdi, et al., Impact of risperidone on leptin and insulin in children and adolescents with autistic spectrum disorders, Clin Biochem (2017), http://dx.doi.org/10.1016/j.clinbiochem.2017.02.003
Contents lists available at ScienceDirect
Clinical Biochemistry journal homepage: www.elsevier.com/locate/clinbiochem
Impact of risperidone on leptin and insulin in children and adolescents with autistic spectrum disorders Pornpen Srisawasdi a,⁎, Natchaya Vanwong b, Yaowaluck Hongkaew b, Apichaya Puangpetch b, Somlak Vanavanan a, Boontarika Intachak a, Nattawat Ngamsamut c, Penkhae Limsila c, Chonlaphat Sukasem b, Martin H. Kroll d a
Division of Clinical Chemistry, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine, Bangkok 10400, Thailand c Yuwaprasart Waithayopathum Child and Adolescent Psychiatric Hospital, Department of Mental Health Services, Ministry of Public Health, Samutprakarn 10270, Thailand d Quest Diagnostics, 3 Giralda Farms, Madison, NJ 07940, USA b
a r t i c l e
i n f o
Article history: Received 6 November 2016 Received in revised form 12 January 2017 Accepted 2 February 2017 Available online xxxx Keywords: Autistic spectrum disorders Risperidone Metabolic risk factors Diabetes Children Adolescent
a b s t r a c t Objective: To evaluate the influence of dose and duration of risperidone treatment on cardiovascular and diabetes risk biomarkers in children and adolescents with autistic spectrum disorders (ASDs). Design and methods: In this cross-sectional analysis, a total of 168 ASDs patients (89% male) treated with a risperidone-based regimen for ≥12 months were included. Blood samples were analyzed for glucose and lipid metabolic markers, adiponectin, leptin, prolactin, cortisol and high sensitive C-reactive protein. Results: The mean concentrations of glucose, insulin, prolactin and leptin and HOMA-IR significantly rose with risperidone dosage (all P b 0.025), but those of adiponectin and cortisol did not. Using regression analysis, insulin, leptin, prolactin and glucose concentrations and HOMA-IR show significant association with dosage. None of the markers except adiponectin showed dependence on duration of treatment. However, insulin and leptin concentrations and HOMA-IR clearly increased with increasing both dosage and duration. Dosage and duration of treatment had minimal effect on standard lipid profile and lipoprotein subclasses. Conclusions: Risperidone treatment disturbed glucose homeostasis and endocrine regulation (particularly leptin) in children and adolescents with ASDs, in a dose- and duration-dependent manner, being suggestive of leptin and insulin resistance mechanisms. Metabolic adverse effects, especially development of type 2 diabetes mellitus should be closely monitored, particularly in individuals receiving high doses and/or long-term risperidone treatment. © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
1. Introduction Autistic spectrum disorders (ASDs) are a complex group of neurodevelopmental disorders with onset prior to 3 years of age [1]. The worldwide prevalence of ASDs in children has increased over the past few decades, ranging from 0.07% to 1.8% [2]. Risperidone is a second-generation antipsychotic drug approved by the US Food and Drug Administration (FDA) to treat ASDs in pediatric patients. It appeared to be the most effective treatment for irritability and aggression in these patients [3–4]. In addition, there has recently been a large increase in the use of risperidone in children with a wide variety of psychiatric and non-psychiatric disorders [5–6]. Consequently, prescriptions for ⁎ Corresponding author at: Division of Clinical Chemistry, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Rama VI Road, Ratchathewi, Bangkok 10400, Thailand. E-mail address: [email protected] (P. Srisawasdi).
risperidone, in particular the off-label therapeutic use in children, have increased dramatically in many countries. Numerous studies have presented associations between antidopaminergic antipsychotic drug therapy and adverse effects, in particular rapid weight gain and metabolic and endocrine abnormalities [7–9]. Although, the specific mechanisms for the metabolic disturbances are not fully understood, children and adolescences appears to experience more adverse effects, even with shorter durations of treatment, than adults [7–8]. The presence of increased appetite during antipsychotic treatment has led investigations to consider a link between increased caloric intake, serotonin, and histamine receptors in the hypothalamus and the accumulation of adipose tissue [10]. Adipose tissue influences the regulation of several important physiological functions through adipokines, including appetite, satiety, energy expenditure, activity, insulin sensitivity and secretion, glucose and lipid metabolism, fat distribution, neuroendocrine regulation, and function of the immune system [11]. Current research proposes that
http://dx.doi.org/10.1016/j.clinbiochem.2017.02.003 0009-9120/© 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Please cite this article as: P. Srisawasdi, et al., Impact of risperidone on leptin and insulin in children and adolescents with autistic spectrum disorders, Clin Biochem (2017), http://dx.doi.org/10.1016/j.clinbiochem.2017.02.003
2
P. Srisawasdi et al. / Clinical Biochemistry xxx (2017) xxx–xxx
2. Materials and methods
using Siemens enzymatic methods (Siemens Medical Solution Diagnostics, Tarrytown, NY, USA). High-sensitivity CRP were measured on the Siemens BN Prospec using the immune nephelometric method, and adiponectin and leptin levels were quantified using a sandwich ELISA system (Mediagnost Gesellschaft für Forschung and Herstellung von Diagnostika GmbH, D-72770 Reutlingen, Germany) [18]. The insulin and prolactin levels were determined using a chemiluminescent immunoassay on the Immulite H2975 (Siemens Medical Solution Diagnostics) and the Architect ci2000 (Abbott Laboratories Abbott Park, IL, USA), respectively. Insulin resistance was estimated using the homeostasis model assessment of insulin resistance (HOMA-IR). The index of HOMA-IR was calculated according to the following formula: HOMAIR = fasting insulin (μU/mL) × fasting glucose (mmol/L) / 22.5. Patient sera were analyzed for lipoprotein subclass using polyacrylamide tube gel electrophoresis (Quantimetrix Lipoprint™, Redondo Beach, CA, USA). This method electrophoretically separates plasma lipoproteins into a maximum of 12 bands ranked by size: very low density (VLDL), midbands [primarily intermediate low density (IDL): MIDC, MIDB and MIDA], large, buoyant LDL (LDL1 and LDL2), small dense LDL (LDL3 to LDL7), and HDL. The relative area for each lipoprotein band was determined by densitometry and multiplied by the total cholesterol concentration to yield the amount of cholesterol for each band. A mean LDL-particle size was computed by integrating the relative contribution of each subfraction of LDL for a given subject.
2.1. Study subjects
2.3. Statistical analyses
A cross-sectional observational study was conducted. During May 2013 to April 2014, we enrolled 168 (149 males and 19 females) Thai children and adolescent outpatients aged between 4 and 18 years from the Yuwaprasart Waithayopathum Child and Adolescent Psychiatric Hospital, Samutprakarn, Thailand, who had been diagnosed with ASDs according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition [1]. Subjects and/or parents/legal guardians were informed of the specific risks and benefits of participation and provided their written consent. The study protocol was approved by the ethics committee of the Faculty of Medicine, Ramathibodi Hospital, Bangkok, Thailand. All participants receiving a risperidone-based regimen for one year or more were enrolled in this study. Demographics and treatment history including dosage and concomitant therapy were extracted from the medical and pharmacy records. Height, weight, and waist circumference measurements were also obtained at enrollment. Exclusion criteria for this study were a known history of pervasive developments disorders, mental retardation, schizophrenia, other psychotic disorders, or conditions associated with convulsions as well as cardiovascular disease, diabetes, cancer, end-stage chronic kidney disease or other serious physical conditions (i.e. thyroid disorders). We excluded patients receiving concomitant treatments that could potentially affect glucose and lipid metabolism. Based on FDA-approved dosing recommendations for pediatric patients [3], we categorized subjects into three groups: low-dose, recommended-dose, and high-dose groups. The recommended starting dose of risperidone is 0.25–0.5 mg/day for patients with body weight b20 kg, or 0.5–1 mg/day for those with body weight of 20 kg or greater. Patients taking less or more than these recommended amounts were classified as receiving low or high doses, respectively.
The clinical data of study subjects were expressed as the medians plus the minimum-maximum range for continuous variables. The chisquare test was used to assess the differences in patient characteristics between boys and girls. Individual group data for all biochemical markers were reported as the mean and standard error of mean (SE), and differences among groups were analyzed using one-way analysis of variance or Mann–Whitney U tests where appropriate. A multiple linear regression model was used to determine the associations between the dosage and duration of treatment and each metabolic risk biomarker. P values b 0.05 were considered statistically significant. All analyses were performed using SPSS, version 15.0 (SPSS Inc., Chicago, IL, USA).
adiponectin and leptin regulate metabolic activity, appetite, and other physiological functions, thus contributing to the development of obesity-related diseases such as type 2 diabetes mellitus (type 2 DM) and cardiovascular disease (CVD) [12]. Adiponectin is abundantly expressed in healthy individuals, has anti-thrombotic, anti-atherogenic, and anti-inflammatory properties, and is down-regulated in obese individuals [13]. Leptin plays an important role in appetite regulation by sympathetic nervous system activation impacting energy homeostasis [14]. Research suggests that antipsychotic medication may affect the common regulatory action of adipokines on appetite, contributing to the development of obesity-related diseases [10,15]. Atherosclerosis begins in childhood. As such, knowledge of the impact of treatments, such as resperidone, is essential for good longterm management of patients into adulthood [16]. Age-inappropriate weight gain and metabolic disturbance in childhood may accelerate or accentuate type 2 DM and CVD, causing premature mortality and morbidity in adults [16–17]. The aim of this cross-sectional observational study was to evaluate the influence of dosage and duration of risperidone treatment on metabolic risk markers in Thai children and adolescents with ASDs. The emphasis was on markers of energy disturbance and cardiovascular disease risk: glucose intolerance, adipokines, dyslipidemia and high-sensitivity C-reactive protein (hsCRP).
3. Results 3.1. Characteristics of the study population The demographic characteristics and biochemical test results of all participants are summarized in Table 1. The majority were male (88.7%), reflecting the more common prevalence of ASD in boys than in girls in the Thai population. More males received a high dose (1.0 mg/day) of risperidone than did females (0.5 mg/day). Median treatment duration was greater in males (62.2 months; interquartile range: 41.5–81.7 months) than females (46.7 months; interquartile range: 30.0–74.1 months). Body mass index (BMI) and waist circumferences were not significantly different between males and females. Although, the mean values of the most biomarkers did not differ significantly between genders, girls presented with greater the levels of leptin and cortisol than males. 3.2. Clinical and biochemical parameters and risperidone dosage
2.2. Biochemical measurements Blood samples were collected as serum or plasma in the fasting state, between the hours of 7 and 10 a.m. All samples were stored at 2-8 °C and analyzed within one day of collection for total cholesterol, triglycerides, low-density lipoprotein-cholesterol (LDL-C), and high-density lipoprotein-cholesterol (HDL-C), creatinine, uric acid, glucose, insulin, adiponectin, leptin, prolactin, and hsCRP. Serum total cholesterol, triglycerides, LDL-C and HDL-C and plasma glucose, were measured
Of these 168 patients, 55 (52 males and 3 females) had a daily dose above FDA recommendation (Table 2), and higher dosage correlated with longer duration. Many of the metabolic risk markers showed statistically significant differences based on the dosage. The mean concentrations of glucose intolerance (fasting glucose, insulin and HOMA-IR) as well as prolactin and leptin rose significantly with increasing daily dosage (all P ≤ 0.022), but those of adiponectin and cortisol did not. Dosage had minimal effect on lipid markers, including triglycerides, total
Please cite this article as: P. Srisawasdi, et al., Impact of risperidone on leptin and insulin in children and adolescents with autistic spectrum disorders, Clin Biochem (2017), http://dx.doi.org/10.1016/j.clinbiochem.2017.02.003
P. Srisawasdi et al. / Clinical Biochemistry xxx (2017) xxx–xxx Table 1 Clinical parameters and biomarker levels.a
Clinical parameter, mean (range) Age, years
Table 2 Clinical and biochemical parameters and risperidone dosage.a
All (n = 168)
Male (n = 149)
Female (n = 19)
10.0 (4.7–17.9) 5.1 (1.8–16.5) 1.0 (0.1–4.0)
10.0 (4.7–17.9) 5.0 (1.8–16.5) 1.0 (0.1–4.0)
10.8 (5.0–16.3) 5.6 (3.0–15.0) 0.5 (0.1–2.0)
0.905
62.2 (17.5–153.6) 19.7 (10.6–38.7) 70.0 (47.0–112.0)
46.7 (14.6–121.3) 16.8 (12.4–35.6) 75.0 (48.5–114.0)
0.146
5.23 (0.04) 8.15 (0.67) 1.911 (0.162) 19.41 (1.24) 8.58 (0.86) 35.7 (2.2) 1.04 (0.04) 4.52 (0.07)
5.12 (0.09) 7.80 (1.79) 1.858 (0.429) 27.23 (7.74) 10.70 (2.87) 35.8 (4.4) 1.01 (0.08) 4.55 (0.20)
0.354 0.971 0.912
1.41 (0.03) 2.81 (0.06)
1.46 (0.10) 2.78 (0.17)
0.641 0.874
0.72 (0.02) 0.45 (0.02) 0.26 (0.01) 0.37 (0.01) 0.91 (0.02) 0.49 (0.02) 0.12 (0.02) 26.93 (0.03) 8.93 (0.46) 2.288 (0.303)
0.63 (0.02) 0.45 (0.03) 0.28 (0.02) 0.39 (0.04) 1.02 (0.07) 0.50 (0.04) 0.09 (0.02) 26.94 (0.09) 12.69 (0.96) 2.292 (1.271)
0.043 0.910 0.551 0.586 0.098 0.889 0.588 0.892 0.005 0.996
Age at starting risperidone, years Risperidone dose, mg/day Duration of treatment, 60.7 months (14.6–153.6) 2 Body mass index, kg/m 19.6 (10.6–38.7) Waist circumference, 70.0 cm (47.0–114.0) Biomarker Fasting glucose, mmol/L 5.22 (0.04) Insulin, μIU/mL 8.14 (0.63) HOMAIR 1.905 (0.151) Prolactin, ng/mL 20.25 (1.38) Leptin, ng/mL 8.85 (0.83) Adiponectin, μg/mL 35.7 (2.0) Triglycerides, mmol/L 1.04 (0.04) Total cholesterol, 4.52 (0.06) mmol/L HDL-C, mmol/L 1.42 (0.03) LDL-C, mmol/L 2.80 (0.06) Lipoprotein subclass (mmol/L) VLDL 0.71 (0.02) MIDC 0.45 (0.01) MIDB 0.26 (0.01) MIDA 0.37 (0.01) LDL1 0.92 (0.02) LDL2 0.50 (0.02) LDL3 to LDL7 0.11 (0.01) LDL-particle size (nm) 26.93 (0.03) Cortisol, μg/dL 9.39 (0.44) hsCRP, mg/L 2.288 (0.303)
3
Risperidone dosage P-value
0.169 0.027
0.275 0.496
0.079 0.402 0.989 0.805 0.880
All biochemical measures are given in Système International units; conversions to conventional units are as follows: fasting glucose (mg/dL), multiply by 18.02, cholesterol (mg/dL), multiply by 38.6, triglycerides (mg/dL), multiply by 88.5. HOMAIR, homeostasis model assessment of insulin resistance; HDL-C, high density lipoprotein-cholesterol; LDL-C, low density lipoprotein–cholesterol; VLDL, very low density lipoprotein; MID, intermediate density lipoprotein midband; hsCRP, high sensitivity Creactive protein. a Data are given as median (minimum-maximum) for clinical parameters and mean (SE) for biomarkers.
cholesterol, HDL-C, LDL-C, and lipoprotein subclasses (all P N 0.10). Although BMI did not vary significantly with risperidone dosage overall, patients treated with a high risperidone dose had a greater mean BMI (22.14 kg/m2) than those treated with a low dose (18.52 kg/m2). Based on comparison between low-dose with high-dose group, leptin shows the highest response, a 270% increase followed by prolactin, a 161% increase, HOMA-IR, a 136% increase, insulin, a 129% increase, adiponectin, a 35% decrease, triglycerides, a 25% increase, HDL-C, a 14% decrease, and glucose, a 5% increase. 3.3. Clinical and biochemical parameters and duration of risperidone therapy We stratified patients into four groups based on the duration of risperidone therapy. The mean dose and BMI markedly increased with long-term risperidone treatment (Table 3). The mean of insulin concentration and HOMA-IR significantly differed among the four groups (all P b 0.025), increasing with longer duration, but fasting glucose did not. Levels of all lipid markers including triglycerides, total cholesterol, HDL-C, LDL-C as well as lipoprotein subclasses did not change
Low dose (n = 18) Clinical parameter Age, years Risperidone dose, mg/day Duration of treatment, months Body mass index, kg/m2 Biomarker Fasting glucose, mmol/L Insulin, μIU/mL HOMAIR Prolactin, ng/mL Leptin, ng/mL Adiponectin, μg/mL Triglycerides, mmol/L Total cholesterol, mmol/L HDL-C, mmol/L LDL-C, mmol/L Lipoprotein subclass (mmol/L) VLDL MIDC MIDB MIDA LDL1 LDL2 LDL3 to LDL7 LDL-particle size (nm) Cortisol, μg/dL hsCRP, mg/L
Recommended dose (n = 95)
9.20 (0.76) 10.86 (0.35)
P-value High dose (n = 55)
11.61 (0.49) 2.066 (0.109) 74.07 (4.11) 22.14 (0.81)
0.056
0.017 0.017
49.3 (7.5) 34.9 (2.5) 0.85 (0.07) 1.06 (0.05) 4.49 (0.20) 4.58 (0.09)
5.29 (0.07) 10.24 (1.31) 2.369 (0.302) 25.06 (2.65) 12.40 (1.85) 32.1 (3.1) 1.06 (0.07) 4.43 (0.10)
1.57 (0.11) 1.43 (0.04) 2.68 (0.17) 2.82 (0.08)
1.35 (0.05) 0.102 2.82 (0.10) 0.777
0.65 (0.02) 0.41 (0.05) 0.25 (0.02) 0.38 (0.03) 0.92 (0.07) 0.48 (0.05) 0.11 (0.02) 26.93 (0.06) 8.52 (0.97) 4.913 (1.910)
0.69 (0.03) 0.45 (0.02) 0.25 (0.01) 0.34 (0.02) 0.90 (0.03) 0.52 (0.03) 0.12 (0.02) 26.91 (0.04) 9.96 (0.81) 2.781 (0.482)
0.253 (0.020) 54.50 (6.59) 18.52 (1.29)
0.751 (0.026) 59.74 (3.11) 20.38 (0.62)
4.92 (0.12) 5.24 (0.04) 4.46 (0.92) 7.71 (0.78) 1.002 1.832 (0.195) (0.217) 11.53 19.11 (1.79) (2.21) 3.35 (1.01) 8.06 (0.94)
0.73 (0.02) 0.46 (0.02) 0.27 (0.01) 0.38 (0.02) 0.93 (0.03) 0.48 (0.02) 0.11 (0.02) 26.94 (0.04) 9.23 (0.60) 1.502 (0.249)
b0.001 0.009 0.058
0.022 0.012 0.003 0.035 0.181 0.589
0.146 0.615 0.418 0.240 0.809 0.558 0.969 0.912 0.597 0.001
Abbreviations as in Table 1. a Data are given as mean (SE).
significantly with duration of therapy. Leptin and hsCRP concentrations increased with duration, although the variation in hsCRP was not statistically significant. Prolactin and cortisol concentrations were not significantly different among treatment duration groups. Based on comparison between duration treatment of less than or = to 24 months with over 96 months, leptin shows the highest response, a 118% increase followed by prolactin, a 113% increase, insulin, a 109% increase, HOMA-IR, a 109% increase, adiponectin, a 57% decrease, triglycerides, a 57% increase, HDL-C, a 20% decrease, and glucose, a 2% decrease. 3.4. Association of dosage and duration of risperidone treatment with metabolic risk markers Table 4 shows the regression coefficients and 95% confidence intervals of dosage and duration of risperidone treatment for biomarkers after adjusting for gender, age and BMI. Insulin, leptin, prolactin, fasting glucose concentrations and HOMA-IR show the significant association with the amount of risperidone dose, while adiponectin, triglycerides, HDL-C and hsCRP did not. None of the markers except adiponectin showed dependence on duration of risperidone treatment in pediatric patients. In addition, we found BMI exerted the strong association
Please cite this article as: P. Srisawasdi, et al., Impact of risperidone on leptin and insulin in children and adolescents with autistic spectrum disorders, Clin Biochem (2017), http://dx.doi.org/10.1016/j.clinbiochem.2017.02.003
4
P. Srisawasdi et al. / Clinical Biochemistry xxx (2017) xxx–xxx
Table 3 Clinical and biochemical parameters and duration of risperidone therapy.a Duration period of risperidone (months)
Clinical parameter Age, years Duration of treatment, months Risperidone dose, mg/day Body mass index, kg/m2 Biomarker Fasting glucose, mmol/L Insulin, μIU/mL HOMAIR Prolactin, ng/mL Leptin, ng/mL Adiponectin, μg/mL Triglycerides, mmol/L Total cholesterol, mmol/L HDL-C, mmol/L LDL-C, mmol/L Lipoprotein subclass (mmol/L) VLDL MIDC MIDB MIDA LDL1 LDL2 LDL3 to LDL7 LDL-particle size (nm) Cortisol, μg/dL hsCRP, mg/L
P-value
0–24 (n = 11)
N24–48 (n = 46)
N48–96 (n = 83)
N96 (n = 28)
7.40 (1.00) 19.72 (0.88) 0.735 (0.158) 17.33 (1.37)
8.95 (0.44) 34.85 (1.04) 0.829 (0.074) 17.26 (0.50)
11.10 (0.30) 68.66 (1.34) 1.297 (0.108) 21.80 (0.70)
14.84 (0.45) 114.70 (3.64) 1.352 (0.169) 24.75 (1.10)
b0.001 b0.001 0.004 b0.001
5.26 (0.12) 5.221 (1.149) 1.216 (0.282) 16.26 (3.94) 6.43 (2.25) 40.1 (7.7) 0.78 (0.08) 4.72 (0.17) 1.57 (0.11) 2.83 (0.19)
5.21 (0.08) 5.555 (0.763) 1.266 (0.166) 22.73 (3.26) 5.98 (1.12) 42.6 (3.6) 1.00 (0.05) 4.75 (0.14) 1.49 (0.06) 2.90 (0.11)
5.27 (0.06) 9.040 (0.876) 2.144 (0.219) 19.64 (1.96) 9.40 (1.27) 36.4 (2.9) 1.05 (0.05) 4.42 (0.09) 1.40 (0.04) 2.71 (0.08)
5.09 (0.09) 10.584 (2.145) 2.453 (0.503) 19.57 (2.09) 13.99 (2.41) 18.1 (2.0) 1.19 (0.11) 4.37 (0.15) 1.27 (0.06) 2.91 (0.16)
0.437 0.021 0.021 0.670 0.019 0.001 0.062 0.107 0.064 0.491
0.68 (0.07) 0.40 (0.03) 0.28 (0.03) 0.45 (0.05) 1.00 (0.05) 0.49 (0.07) 0.07 (0.02) 27.06 (0.06) 10.12 (0.76) 0.862 (0.268)
0.74 (0.03) 0.50 (0.03) 0.29 (0.02) 0.39 (0.02) 0.95 (0.04) 0.50 (0.03) 0.12 (0.04) 26.93 (0.06) 9.20 (0.79) 1.506 (0.554)
0.69 (0.02) 0.44 (0.02) 0.25 (0.01) 0.35 (0.02) 0.89 (0.03) 0.49 (0.02) 0.12 (0.02) 26.89 (0.04) 8.84 (0.63) 2.677 (0.442)
0.72 (0.04) 0.41 (0.02) 0.26 (0.01) 0.36 (0.02) 0.94 (0.05) 0.51 (0.05) 0.11 (0.02) 26.98 (0.04) 11.54 (1.34) 3.007 (0.841)
0.620 0.070 0.077 0.087 0.495 0.986 0.791 0.350 0.243 0.167
Abbreviations as in Table 1. a Data are given as mean (SE).
Table 4 Association of BMI, dose and duration period of risperidone with metabolic risk factors. Dependent variable Insulin BMI Risperidone dose, mg/day Duration of treatment, months HOMAIR BMI Risperidone dose, mg/day Duration of treatment, months Leptin BMI Risperidone dose, mg/day Duration of treatment, months Adiponectin BMI Risperidone dose, mg/day Duration of treatment, months Prolactin BMI Risperidone dose, mg/day Duration of treatment, months Glucose BMI Risperidone dose, mg/day Duration of treatment, months hsCRP BMI Risperidone dose, mg/day Duration of treatment, months a
Regression coefficienta
95% confidence interval
P-value
0.602 1.597 0.034
0.391 to 0.813 0.081 to 3.113 −0.018 to 0.087
b0.001 0.039 0.195
0.143 0.402 0.009
0.091 to 0.194 0.031 to 0.773 −0.003 to 0.022
b0.001 0.034 0.149
1.256 1.958 0.000
1.072 to 1.439 0.584 to 3.332 −0.046 to 0.046
b0.001 0.006 0.995
−1.702 2.047 −0.206
−2.326 to −1.078 −2.662 to 6.756 −0.363 to −0.050
b0.001 0.391 0.010
0.025 5.372 −0.055
−0.496 to 0.547 1.817 to 8.926 −0.189 to 0.079
0.923 0.003 0.420
0.124 2.496 0.012
−0.133 to 0.381 0.743 to 4.250 −0.054 to 0.078
0.369 0.005 0.800
0.280 0.134 0.009
0.169 to 0.391 −0.651 to 0.919 −0.020 to 0.037
b0.001 0.736 0.535
Data are from multivariable linear regression analyses, adjusted for gender and age.
with the concentrations of insulin, leptin, adiponectin, triglycerides, HDL-C and hsCRP but not with prolactin and fasting glucose concentrations. 3.5. Effect of dosage and duration of risperidone treatment on metabolic risk markers To assess the effect of both dosage and duration of treatment on metabolic risk factors, the geometric means of each marker concentration based on the administration of low-dose, recommended-dose and high-dose in four duration groups were calculated (Fig. 1). No subject in the high-dose group had been treated for less than or = to 24 months. A similar pattern occurred with insulin (Fig. 1A) and leptin (Fig. 1C) concentration and HOMA-IR (Fig. 1B), all clearly increased with dosage and duration. The geometric mean of prolactin level (Fig. 1E) was higher in the high-dose than in the low-dose, especially in the group treated for 48 to 96 months (P-value = 0.004) and was not associated with duration. Similar findings were seen with fasting glucose concentration (Fig. 1F). The geometric means of adiponectin (Fig. 1D) appeared decreasing with duration. Risperidone dosage increases the percentage of subjects who exceed age-specific reference intervals for glucose, insulin resistance, leptin, triglycerides and HDL-C (Table 5). Also, risperidone duration causes the same effects for leptin (Table 5). For both dosage and duration, the increases are significant. 4. Discussion Risperidone is a drug widely prescribed for children and adolescents with ASDs. Discontinuation is associated with resurgence of aggression, so long-life medication is recommended [22]. Because of differences in absorption, distribution, and metabolism, children require a higher dose per kilogram weight to achieve efficacy similar to that in adults [8]. Little is known about potential dose and duration-related effects of
Please cite this article as: P. Srisawasdi, et al., Impact of risperidone on leptin and insulin in children and adolescents with autistic spectrum disorders, Clin Biochem (2017), http://dx.doi.org/10.1016/j.clinbiochem.2017.02.003
P. Srisawasdi et al. / Clinical Biochemistry xxx (2017) xxx–xxx
5
Fig. 1. Effect of dosage and duration of risperidone treatment on metabolic risk markers.
risperidone medication on metabolic, diabetes, and endocrine disturbances in these vulnerable populations. With regards to risperidone-induced endocrine disturbances, increased prolactin has been the most common observation [23]. As expected, in our subjects, we observed prolactin elevations associated with dose. Besides prolactin, the dose significantly and clinically affected glucose, insulin, HOMA-IR, and leptin, independent of BMI (Table 4). Although, long-term therapy increased leptin, insulin, and HOMA-IR, the results were not statistically significant with the duration after adjusting for age, gender and BMI. Adiponectin showed a decrease,
dependent on duration, but not dose, suggesting that the mechanism for action works indirectly by decreasing satiety and ultimately increasing food intake, thus resulting in increased body adiposity. Studies suggest increase in appetite results in increased adipose tissue followed by metabolic impairments [7–8]. According to Teff KL et al., short-term administration of olanzapine and aripiprazole directly affects tissue function, enhancing peripheral insulin resistance, independent of weight gain in healthy subjects [24]. In a study on eating behavior, they found antipsychotic-induced metabolic changes preceded decreasing satiety, which they thought was caused by central insulin
Table 5 Percentage of patients exceeded age-specific reference intervals of metabolic risk biomarkers.
Hyperglycemiaa, % Increased insulin resistanceb, % Hyperleptinemiac, % TG ≥1.70 mmol/Ld, % HDL-C b 1.03 mmol/Le, % a b c d e
All (n = 168)
Risperidone dosage
Duration period of risperidone (months)
Low dose (n = 18)
Recommended dose (n = 95)
High dose (n = 55)
0–24 (n = 11)
N24–48 (n = 46)
N48–96 (n = 83)
N96 (n = 28)
22.6 22.7 45.8 9.5 16.1
11.1 11.1 28.6 0 11.1
19.0 20.5 44.9 9.4 16.8
32.7 30.6 54.1 12.73 16.4
18.2 22.2 28.6 0 18.2
21.7 17.5 44.4 2.2 10.9
24.1 25.7 45.0 12.0 18.1
21.4 22.2 58.8 17.9 17.9
Defined using the International Diabetes Federation (IDF) [19] as glucose ≥5.6 mmol/L. Defined as HOMA-IR ≥95th percentile age-specific reference intervals [20]. Defined as leptin ≥95th percentile age, sex and BMI-specific reference intervals [18,21]. Defined using the International Diabetes Federation (IDF) [19] as triglycerides ≥1.7 mmol/L. Defined using the International Diabetes Federation (IDF) [19] as HDL-C b 1.03 mmol/L.
Please cite this article as: P. Srisawasdi, et al., Impact of risperidone on leptin and insulin in children and adolescents with autistic spectrum disorders, Clin Biochem (2017), http://dx.doi.org/10.1016/j.clinbiochem.2017.02.003
6
P. Srisawasdi et al. / Clinical Biochemistry xxx (2017) xxx–xxx
and leptin resistance [25]. Here, based on our study in children and adolescents ASDs with long-term risperidone treatment, the data indicate that risperidone dosage is strongly associated with increased leptin and insulin, but not with adiponectin and BMI. Moreover, in response to risperidone treatment, based on comparison between low-dose and highdose, leptin markedly increased (270%) while adiponectin decreased (35%). Based on the comparison between duration treatment of less than or = to 24 months with over 96 months, leptin also markedly increased (118%) and adiponectin decreased (57%). It is well known that circulating leptin as well as adiponectin levels are considered to be proportional to adipose tissue mass. Consequently, we suggest that risperidone acts through leptin and insulin pathways independent of body adiposity. Risperidone appears to interfere with the leptin regulatory system, because the leptin is increased but the actions of leptin, appetite decrease and increased adipose tissue utilization, are hampered. Even though risperidone may cause increased fat deposition, as indicated by the increase in BMI, the marked increase in leptin along with weight-gain suggests that a potential mechanism may work through the development of leptin resistance. Risperidone may act directly or indirectly on the leptin receptor. Cheng et al. have demonstrated that palmitic acid in mice can inhibit leptin signaling in the paraventricular nucleus of the hypothalamus, induces an inflammatory response in the hypothalamus, and attenuate the central leptin regulation on hepatic glucose and lipid metabolism [26]. In a similar fashion, arachidonic acid reduces central leptin sensitivity, inhibits leptin signaling in the paraventricular nucleus of the hypothalamus, stimulates pro-inflammatory responses in the same area, and attenuates the central leptin action on hepatic glucose and lipid metabolism [27]. Risperidone may share some structural similarities to palmitic or arachidonic acid and thus mimic these two molecules ability to cause leptin resistance. In patients treated with second generation antipsychotics, numerous studies demonstrated that the link of increased appetite to weight gain may be explained by interaction with dopamine receptors [28]. A homeostatic mechanism for coordinating the status of energy stores is relayed by neurohormones, which are modulated by leptin and insulin. Neurohormones coordinate energy stores acting through insulin and leptin, which share receptors; consequently, risperidone may impair both hormonal actions [29–30]. The mechanism of risperidone-induced insulin and leptin resistance may act through the inhibition of dopamine D2 receptors regulating intercellular cyclic adenosine 3monophosphate accumulation, inhibiting insulin-induced protein kinase B phosphorylation and activation of transcription 3-phosphorylation [31]. The concept of leptin resistance is analogous to the syndrome of insulin resistance, in which elevated levels of leptin could result in the false perception that fat stores are inadequate, leading to increased food consumption. Additional adipose tissue by exceeding the level of energy intake over the level of energy expenditure will provide a worsening of the leptin and insulin resistance. Furthermore, leptin has several effects on the glucose-insulin homeostasis, such as directly regulating pancreatic β-cells and insulin-sensitive tissues, independently of its effects on adiposity [32]. Consequently, the failure of elevated leptin levels to suppress food intake and energy expenditure may promote insulin resistance in risperidone-treated patients. An alteration of adipokines and increased insulin and leptin resistances resulted in a vicious cycle of increased adipose tissue and leptin and insulin resistance. In our study, we found the mean concentration of leptin in boys was lower than in girls which is consistent with other studies [33–34]. Garcia-Mayor et al. reported the age-related changes of leptin in healthy boys after the age of 10 years declines as testosterone increases [33]. In the present work, the levels of leptin rose progressively in chronically treated patients (the mean age of 15.04 years) with high risperidone dose (Fig. 1). Interestingly, a similar pattern occurred with insulin levels. It appears treatment disturbs the leptin and insulin regulatory systems, in a dose- and duration-dependent manner, suggesting that both
hormones are the key agents of interest. Because strong associations link leptin, insulin, HOMA-IR and adiponectin with BMI (Table 4), a complex network exists, supporting the concept that risperidone plays a role in appetite regulation and the communication of energy needs between the central nervous system and adipose tissue resulting in individual weight gain [35]. Despite the evidence of insulin resistance among Thai children and adolescent ASDs treated with risperidone, evidence of type 2 DM as defined by fasting plasma glucose ≥7.0 mmol/L (to convert to mg/dL, multiply by 18.02) was not observed with therapy up to 153.6 months. Glucose showed a slight response to risperidone treatment, changing only 2–8%. The failure of glucose to change in value, while insulin increases strongly, suggests insulin resistance, which may represent a pre-diabetec state. This is not surprising given that the development of type 2 DM is a progressive process that manifests over many years and perhaps decades [36]. Nevertheless, we found a clear association between dose and plasma glucose, consistent with global studies in pediatric populations [17,37]. The alteration of glucose homeostasis in childhood causes a rapid onset of type 2 DM later in adulthood. Interestingly, our results indicated that the concentration of fasting plasma glucose was not significantly related with BMI. It is, thus, tempting to assume that treated-risperidone among children and adolescents with the particular high-doses and long-term medication may induce a high rate in development of type 2 DM that might potentially occur without change in body weight. Risperidone dosage showed a limited effect while duration a mild effect on BMI (Tables 2 and 3). Such a response could be aligned with the lower prevalence of metabolic syndrome in the adult Asian population [38]. Patients with low dose or duration risperidone did not exceed age-specific interval for triglycerides (Table 5). In contrast, even at low dose or duration, the percentage of subjects with hyperglycemia and increased insulin resistance (markers of prediabetes) was increased (Table 5). The most alarming finding was that at high-dose or long-duration risperidone treatment, the percentage of subjects exceeding the age-specific reference intervals was N50% (Table 5). Both insulin and leptin resistance contribute to cardio-metabolic risk by disturbing of carbohydrate and lipid metabolism [39]. Besides diabetes, dyslipidemia is of concern upon the administration of antipsychotic drugs in children and adolescents. Triglycerides and HDL-C are the main lipid biomarkers for cardiometabolic risk during antipsychotics treatment [7]. Interestingly, our results did not show significant changes for triglycerides, HDL-C, and small dense LDL in association with dosage and duration treatment of risperidone in youths with ASDs. Moreover, most patients had plasma lipid and lipoprotein concentrations similar to that of general healthy population. We observed an increase triglycerides and decrease in HDL with longer duration of treatment (Table 3). Thus, it is possible that resperidone-induced insulin and leptin resistances may influence cardiometabolic pathways. In addition, significant weight gain appeared to be more prevalence in these patients, perhaps based on obesity playing a central role among metabolic disturbances including insulin resistance, hypertension and inflammation. Consequently, drug-induced metabolic abnormality in childhood may enhance a development of cardiometabolic disorders later in adulthood. Limitations of this study include that it was cross-sectional in design and based on an Asian population. Longitudinal observations in drugnaïve patients that will be adequately powered for demonstrating an association of risperidone therapy and metabolic side effects is warranted. The study did not include other ethnicities. It is possible that ethnicity and individual-specific thresholds might be haven different genetic variant for metabolize of risperidone in pediatric patients. A major metabolizing enzyme of risperidone is cytochrome P 2D6 [40], thus, presence of its various phenotypes can lead to decrease or elevate metabolism and elimination of risperidone which may contribute to drug-increased metabolic adverse effects. Future studies including other ethnicities and individual-pharmacogenomic of risperidone may provide additional information.
Please cite this article as: P. Srisawasdi, et al., Impact of risperidone on leptin and insulin in children and adolescents with autistic spectrum disorders, Clin Biochem (2017), http://dx.doi.org/10.1016/j.clinbiochem.2017.02.003
P. Srisawasdi et al. / Clinical Biochemistry xxx (2017) xxx–xxx
In conclusion, risperidone dose in the treatment for autistic spectrum disorders in children and adolescents affect leptin and insulin. Our findings highlight that risperidone therapy directly and adversely impacts glucose homeostasis by inhibiting the actions of leptin and insulin. Risperidone-induced abnormalities in leptin and insulin resistance result in adipose tissue accumulation, which in turn can lead to complications of lipid metabolism and cardiovascular disease. These effects are related to treatment dose. The adverse metabolic changes associated with risperidone treatment suggest that risk for metabolic adverse effects, especially development of type 2 diabetes mellitus and adipose regulation should be closely monitored, particularly in patients receiving high doses and long-term treatment. Because of interindividual variability in risperidone metabolism, the resulting plasma concentration at a given dose cannot be predicted by the dose. Thus, the monitoring its level would affords the opportunity to limit long term impact of these side effects. In addition, pursuit of therapeutic interventions that specifically enhance the actions of leptin and insulin could improve patient management and reduce the risk of cardiovascular complications.
[8]
[9]
[10]
[11] [12] [13]
[14]
[15]
[16]
Funding [17]
This study was supported by research grants of 1) the Faculty of Medicine, Ramathibodi Hospital, Mahidol University (56076), Thailand, 2) Khun Poom Foundation, a project under Her Royal Highness Princess Ubonratana Rajakanya Siriwatana Bhanawadee and 3) the National Research Council of Thailand (92/2558).
[18] [19] [20]
Conflicts of interest [21]
The authors declare no conflicts of interest related to this article. [22]
Author contributions All authors confirm they have contributed to the intellectual content of this paper and have met the following requirements: (a) providing a significant contribution to the conception, design and conduct of the study and the data collection, analysis and interpretation; (b) participating in the drafting or revision of the article for intellectual content; and (c) granting final approval of the article.
[23]
[24]
[25]
[26]
Acknowledgments The authors gratefully acknowledge the staff of Yuwaprasart Waithayopathum Child and Adolescent Psychiatric Hospital and Jirapa Kerdmongkol at the Department of Pathology, Ramathibodi Hospital, Mahidol University for their assistance. We wish to thank all the children and adolescents with ASDs who took part in this study. References [1] American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders (4th ed., text revision), American Psychiatric Association, Washington, DC, 2000 70–75. [2] Centers for Disease Control and Prevention, Prevalence of autism spectrum disorders—Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008, MMWR Surveill. Summ. 61 (3) (Mar 30, 2012) 1–19. [3] FDA Approves the First Drug to Treat Irritability Associated With Autism, Risperdal, US Food and Drug Administration, April 5, 2013 Web site. http://www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/2006/ucm108759.htm. Updated. (Accessed June 24, 2016). [4] A. Gagliano, E. Germanò, G. Pustorino, et al., Risperidone treatment of children with autistic disorder: effectiveness, tolerability, and pharmacokinetic implications, J Child Adolesc Psychopharmacol 14 (1) (2004) 39–47. [5] R.B. Penfold, C. Stewart, E.M. Hunkeler, et al., Use of antipsychotic medications in pediatric populations: what do the data say? Curr. Psychiatry Rep. 15 (12) (2013) 426. [6] L. Carton, O. Cottencin, M. Lapeyre-Mestre, et al., Off-label prescribing of antipsychotics in adults, children and elderly individuals: a systematic review of recent prescription trends, Curr. Pharm. Des. 21 (23) (2015) 3280–3297. [7] M. De Hert, M. Dobbelaere, E.M. Sheridan, et al., Metabolic and endocrine effects of second-generation antipsychotic in children and adolescents: a systematic review of
[27] [28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
7
randomized, placebo controlled trials and guidelines for clinical practice, Eur. Psychiatry 26 (3) (2011) 144–158. R. Ronsley, D. Nguyen, J. Davidson, et al., Increased risk of obesity and metabolic dysregulation following 12 months of second-generation antipsychotic treatment in children: a prospective cohort study, Can. J. Psychiatr. 60 (10) (2015) 441–450. D.M. Rubin, A.R. Kreider, M. Matone, et al., Risk for incident diabetes mellitus following initiation of second-generation antipsychotics among Medicaid-enrolled youths, JAMA Pediatr. 169 (4) (2015), e150285. L.A. Maayan, J. Vakhrusheva, Risperidone associated weight, leptin, and anthropometric changes in children and adolescents with psychotic disorders in early treatment, Hum. Psychopharmacol. 25 (2) (2010) 133–138. H.K. Park, R.S. Ahima, Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism, Metabolism 64 (1) (2015) 24–34. Y. Matsuzawa, Establishment of a concept of visceral fat syndrome and discovery of adiponectin, Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 86 (2) (2010) 131–141. A. Alikaşifoğlu, N. Gönç, Z.A. Özön, et al., The relationship between serum adiponectin, tumor necrosis factor-alpha, leptin levels and insulin sensitivity in childhood and adolescent obesity: adiponectin is a marker of metabolic syndrome, J. Clin. Res. Pediatr. Endocrinol. 1 (5) (2009) 233–239. H.S. Moon, M. Dalamaga, S.Y. Kim, et al., Leptin's role in lipodystrophic and nonlipodystrophic insulin-resistant and diabetic individuals, Endocr. Rev. 34 (3) (2013) 377–412. Z.J. Zhang, Z.J. Yao, W. Liu, et al., Effects of antipsychotics on fat deposition and changes in leptin and insulin levels. Magnetic resonance imaging study of previously untreated people with schizophrenia, Br. J. Psychiatry 184 (2004) 58–62. M. De Hert, J. Detraux, R. van Winkel, et al., Metabolic and cardiovascular adverse effects associated with antipsychotic drugs, Nat. Rev. Endocrinol. 8 (2) (2011) 114–126. W.V. Bobo, W.O. Cooper, C.M. Stein, et al., Antipsychotics and the risk of type 2 diabetes mellitus in children and youth, JAMA Psychiat. 70 (10) (2013) 1067–1075. Leptin, Mediagnost Gesellschaft für Forschung and Herstellung von Diagnostika, Leptin Sensitive ELISA Assay Kit product No. E077. GmbH, D-72770 Reutlingen, Germany. P. Zimmet, K.G. Alberti, F. Kaufman, et al., The metabolic syndrome in children and adolescents – an IDF consensus report, Pediatr. Diabetes 8 (2007) 299–306. P. Allard, E.E. Delvin, G. Paradis, et al., Distribution of fasting plasma insulin, free fatty acids, and glucose concentrations and of homeostasis model assessment of insulin resistance in a representative sample of Quebec children and adolescents, Clin. Chem. 49 (4) (2003) 644–649. N. Kiatsopit, O. Panamonta, C. Suesirisawat, et al., The age of onset of pubertal development in healthy Thai boys in Khon Kaen, Thailand, Asian Biomed. 9 (2) (2015) 225–229. Research Units on Pediatric Psychopharmacology Autism Network, Risperidone treatment of autistic disorder: longer-term benefits and blinded discontinuation after 6 months, Am. J. Psychiatry 162 (7) (2005) 1361–1369. Y. Roke, P.N. van Harten, A.M. Boot, J.K. Buitelaar, Antipsychotic medication in children and adolescents: a descriptive review of the effects on prolactin level and associated side effects, J. Child Adolesc. Psychopharmacol. 19 (4) (2009) 403–414. K.L. Teff, M.R. Rickels, J. Grudziak, et al., Antipsychotic-induced insulin resistance and postprandial hormonal dysregulation independent of weight gain or psychiatric disease, Diabetes 62 (9) (2013) 3232–3240. K.L. Teff, K. Rickels, E. Alshehabi, et al., Metabolic impairments precede changes in hunger and food intake following short-term administration of second-generation antipsychotics, J. Clin. Psychopharmacol. 35 (5) (2015) 579–582. L. Cheng, Y. Yu, A. Szabo, et al., Palmitic acid induces central leptin resistance and impairs hepatic glucose and lipid metabolism in male mice, J. Nutr. Biochem. 26 (5) (2015) 541–548. L. Cheng, Y. Yu, H. Wang, et al., Arachidonic acid impairs hypothalamic leptin signaling and hepatic energy homeostasis in mice, Mol. Cell. Endocrinol. 412 (2015) 12–18. A. Esen-Danaci, A. Sarandol, F. Taneli, et al., Effects of second generation antipsychotics on leptin and ghrelin, Prog. Neuro-Psychopharmacol. Biol. Psychiatry 32 (6) (2008) 1434–1438. K.D. Niswender, D.G. Baskin, M.W. Schwartz, Insulin and its evolving partnership with leptin in the hypothalamic control of energy homeostasis, Trends Endocrinol. Metab. 15 (8) (2004) 362–369. C. Kursungoz, M. Ak, T. Yanik, Effects of risperidone treatment on the expression of hypothalamic neuropeptide in appetite regulation in Wistar rats, Brain Res. 1596 (2015) 146–155. L. Piao, J. Park, Y. Li, et al., SOCS3 and SOCS6 are required for the risperidone-mediated inhibition of insulin and leptin signaling in neuroblastoma cells, Int. J. Mol. Med. 33 (5) (2014) 1364–1370. S.D. Covey, R.D. Wideman, C. McDonald, et al., The pancreatic beta cell is a key site for mediating the effects of leptin on glucose homeostasis, Cell Metab. 4 (4) (2006) 291–302. R.V. Garcia-Mayor, M.A. Andrade, M. Rios, et al., Serum leptin levels in normal children: relationship to age, gender, body mass index, pituitary-gonadal hormones, and pubertal stage, J. Clin. Endocrinol. Metab. 82 (9) (1997) 2849–2855. C.S. Mantzoros, J.S. Flier, A.D. Rogol, A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. V. Rising leptin levels may signal the onset of puberty, J. Clin. Endocrinol. Metab. 82 (4) (1997) 1066–1070. M. Cnop, M.J. Landchild, J. Vidal, et al., The concurrent accumulation of intra-abdominal and subcutaneous fat explains the association between insulin resistance and plasma leptin concentrations: distinct metabolic effects of two fat compartments, Diabetes 51 (4) (2002) 1005–1015. J.B. Meigs, D.C. Muller, D.M. Nathan, et al., Baltimore longitudinal study of aging the natural history of progression from normal glucose tolerance to type 2 diabetes in the Baltimore longitudinal study of aging, Diabetes 52 (5) (2003) 1475–1484.
Please cite this article as: P. Srisawasdi, et al., Impact of risperidone on leptin and insulin in children and adolescents with autistic spectrum disorders, Clin Biochem (2017), http://dx.doi.org/10.1016/j.clinbiochem.2017.02.003
8
P. Srisawasdi et al. / Clinical Biochemistry xxx (2017) xxx–xxx
[37] C. Panagiotopoulos, R. Ronsley, J. Davidson, Increased prevalence of obesity and glucose intolerance in youth treated with second-generation antipsychotic medications, Can. J. Psychiatr. 54 (11) (2009) 743–749. [38] R.B. Khalil, Atypical antipsychotic drugs, schizophrenia, and metabolic syndrome in non-Euro-American societies, Clin. Neuropharmacol. 35 (2012) 141–147.
[39] H. Zuo, Z. Shi, B. Yuan, et al., Association between serum leptin concentrations and insulin resistance: a population-based study from China, PLoS One 8 (1) (2013), e54615. [40] J. van der Weide, J. van Baalen-Benedek, E.H. Kootstra-Ros, et al., Metabolic ratios of psychotropics as indication of cytochrome P450 2D6/2C19 genotype, Ther. Drug Monit. 27 (4) (2005) 478–483.
Please cite this article as: P. Srisawasdi, et al., Impact of risperidone on leptin and insulin in children and adolescents with autistic spectrum disorders, Clin Biochem (2017), http://dx.doi.org/10.1016/j.clinbiochem.2017.02.003